FBXW7c.1394G>ALikely pathogenic

Print report

Variant interpretation report

FBXW7 c.1394G>A, p.(Arg465His)

NM_033632.3:c.1394G>A NP_361014.1:p.(Arg465His) View identifiers

Classification

Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About FBXW7

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 strong (pathogenic) · 1 moderate (pathogenic) · 2 supporting (pathogenic)
Expert rules: Not recorded
Pipeline record: 19 Jul 2026 · version 7.0.4

Evidence considered

View criteria

Applied evidence criteria

PS3 (strong): Two independent publications directly tested the R465H variant in functional assays and demonstrated unequivocal loss of E3 ubiquitin ligase function. PMID:17575125 showed R465H is severely deficient in Notch1 ICD polyubiquitylation and fails to suppress Notch1 signaling in a luciferase reporter assay. PMID:23228967 independently demonstrated R465H is severely deficient in polyubiquitylating GRα. Two independent studies testing the exact variant with unequivocal functional defect meets the strong strength threshold.
PM1 (moderate): Arg465 is located on the surface of the WD40 β-propeller domain, the substrate-recognition pocket of FBXW7 critical for E3 ubiquitin ligase function. PMID:17575125 explicitly identifies Arg465 as a residue on the β-propeller surface essential for substrate recognition. The residue is in a statistically significant hotspot per cancerhotspots.org. The WD40 domain is a well-characterized functional domain without benign variation at structurally critical arginine positions.
PM2 (supporting): NM_033632.3:c.1394G>A is absent from gnomAD v2.1 (0/231,580 alleles) and gnomAD v4.1 (0/1,593,060 alleles), yielding an allele frequency of 0% in all populations. This is well below the PM2 threshold of <0.1% for a rare variant absent from population databases.
PP3 (supporting): REVEL score of 0.557 exceeds the 0.5 threshold predictive of a damaging effect. BayesDel score of 0.112528 is below the typical 0.27 threshold and HCI prior is unavailable. SpliceAI predicts no splice impact (max delta=0.00). Despite mixed in silico results, the REVEL score provides one line of computational support for a deleterious effect.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 4 Benign evidence criteria: 0

Pathogenic criteria applied · 4

PS3Strong

PS3 · strong

Two independent publications directly tested the R465H variant in functional assays and demonstrated unequivocal loss of E3 ubiquitin ligase function. PMID:17575125 showed R465H is severely deficient in Notch1 ICD polyubiquitylation and fails to suppress Notch1 signaling in a luciferase reporter assay. PMID:23228967 independently demonstrated R465H is severely deficient in polyubiquitylating GRα. Two independent studies testing the exact variant with unequivocal functional defect meets the strong strength threshold.

PM1Moderate

PM1 · moderate

Arg465 is located on the surface of the WD40 β-propeller domain, the substrate-recognition pocket of FBXW7 critical for E3 ubiquitin ligase function. PMID:17575125 explicitly identifies Arg465 as a residue on the β-propeller surface essential for substrate recognition. The residue is in a statistically significant hotspot per cancerhotspots.org. The WD40 domain is a well-characterized functional domain without benign variation at structurally critical arginine positions.

PM2Supporting

PM2 · supporting

NM_033632.3:c.1394G>A is absent from gnomAD v2.1 (0/231,580 alleles) and gnomAD v4.1 (0/1,593,060 alleles), yielding an allele frequency of 0% in all populations. This is well below the PM2 threshold of <0.1% for a rare variant absent from population databases.

PP3Supporting

PP3 · supporting

REVEL score of 0.557 exceeds the 0.5 threshold predictive of a damaging effect. BayesDel score of 0.112528 is below the typical 0.27 threshold and HCI prior is unavailable. SpliceAI predicts no splice impact (max delta=0.00). Despite mixed in silico results, the REVEL score provides one line of computational support for a deleterious effect.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 strong, PM1 moderate, PM2 supporting, PP3 supporting; combination = 1 strong + 1 moderate + 2 supporting, which maps to Likely Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

0 / 1,593,060 alleles

gnomAD v4.1: 0 / 1,593,060 alleles. Recorded AF 0. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/231580 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/14564 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded. ClinVar API review status: criteria provided, single submitter.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Applied · PS3 → OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

311 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV55891746, n = 311 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 4 met · 12 not met · 7 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_033632.3:c.1394G>A (p.Arg465His) in FBXW7 is a missense variant in the WD40 substrate-recognition domain of this E3 ubiquitin ligase tumor suppressor.

Two independent publications demonstrate that the R465H substitution severely impairs FBXW7 ubiquitin ligase activity: deficient in Notch1 ICD polyubiquitylation (PMID:17575125) and deficient in GRα polyubiquitylation (PMID:23228967), meeting PS3 at strong strength.

Arg465 is located on the surface of the WD40 β-propeller, the substrate-binding pocket critical for FBXW7 function, in a statistically significant mutational hotspot, meeting PM1 at moderate strength.

The variant is absent from gnomAD v2.1 (0/231,580 alleles) and v4.1 (0/1,593,060 alleles), meeting PM2 at supporting strength.

REVEL in silico prediction score of 0.557 supports a deleterious effect, meeting PP3 at supporting strength.

Applying generic ACMG/AMP 2015 combination rules: 1 strong (PS3) + 1 moderate (PM1) + 2 supporting (PM2, PP3) classifies this variant as Likely Pathogenic.

Met · 4

PS3 StrongTwo independent publications directly tested the R465H variant in functional assays and demonstrated unequivocal loss of E3 ubiquitin ligase function. PMID:17575125 showed R465H is severely deficient in Notch1 ICD polyubiquitylation and fails to suppress Notch1 signaling in a luciferase reporter assay. PMID:23228967 independently demonstrated R465H is severely deficient in polyubiquitylating GRα. Two independent studies testing the exact variant with unequivocal functional defect meets the strong strength threshold. Details ▾Hide ▴

Evidence considered

R465H mutant severely deficient in Notch1 ICD ubiquitylation vs wild-type hCdc4 (PMID:17575125
Fig 1D)
R465H mutant fails to suppress Notch1 transcriptional activity in luciferase reporter assay (PMID:17575125
Fig 2A-B)
R465H mutant severely deficient in GRα polyubiquitylation vs wild-type FBXW7 (PMID:23228967
Fig 3c)
R465H found in 3/26 pediatric T-ALL patients
absent in matched normal DNA indicating somatic origin (PMID:17575125
Table 1)

Still missing

Functional assays performed in somatic cancer context (T-ALL)
not germline disease models
Assays are in vitro (ubiquitylation
luciferase reporter) rather than physiological in vivo models

Sources

PMID:17575125 ↗PMID:23228967 ↗

PM1 ModerateArg465 is located on the surface of the WD40 β-propeller domain, the substrate-recognition pocket of FBXW7 critical for E3 ubiquitin ligase function. PMID:17575125 explicitly identifies Arg465 as a residue on the β-propeller surface essential for substrate recognition. The residue is in a statistically significant hotspot per cancerhotspots.org. The WD40 domain is a well-characterized functional domain without benign variation at structurally critical arginine positions. Details ▾Hide ▴

Evidence considered

Arg465 located on the surface of the WD40 β-propeller
the substrate-binding pocket (PMID:17575125)
Residue in statistically significant hotspot (cancerhotspots.org)
WD40 domain critical for substrate recognition in SCF E3 ubiquitin ligase complex
OncoKB classifies variant as Likely Oncogenic with loss-of-function effect

Sources

PMID:17575125 ↗oncokb ↗

PM2 SupportingNM_033632.3:c.1394G>A is absent from gnomAD v2.1 (0/231,580 alleles) and gnomAD v4.1 (0/1,593,060 alleles), yielding an allele frequency of 0% in all populations. This is well below the PM2 threshold of <0.1% for a rare variant absent from population databases. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: 0/231
580 alleles
AF=0.000%
gnomAD v4.1: 0/1
593
060 alleles
Absent from all subpopulations including best subpop (African/African American)

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

PP3 SupportingREVEL score of 0.557 exceeds the 0.5 threshold predictive of a damaging effect. BayesDel score of 0.112528 is below the typical 0.27 threshold and HCI prior is unavailable. SpliceAI predicts no splice impact (max delta=0.00). Despite mixed in silico results, the REVEL score provides one line of computational support for a deleterious effect. Details ▾Hide ▴

Evidence considered

REVEL: 0.557 (deleterious
above 0.5 threshold)
BayesDel: 0.112528 (below 0.27 deleterious threshold)
SpliceAI max delta: 0.00 (no predicted splice impact)

Still missing

HCI prior not available for this gene
Mixed in silico predictions — REVEL supports
BayesDel does not

Sources

revelbayesdelspliceai ↗

Not met · 12 · evaluated, threshold not reached

PS1 No evidence of a different pathogenic amino acid change at codon 465 with established pathogenicity. The pm5_candidates search found no same-residue comparator variants with expert panel pathogenic classification in ClinVar. Details ▾Hide ▴

Evidence considered

No comparator variant at Arg465 with established pathogenicity in ClinVar

Still missing

No ClinVar entries for alternate pathogenic missense changes at Arg465

Sources

pm5_candidates

PP5 ClinVar variation 4530533 is classified as 'Tier I - Strong' with review status 'criteria provided, single submitter' (1 star). The user's PP5 rule requires ClinVar 3-star expert panel review to apply PP5 at supporting strength. A 1-star single-submitter classification does not meet this threshold. Details ▾Hide ▴

Evidence considered

ClinVar ID 4530533: Tier I - Strong
single submitter (1 star)

Still missing

No 3-star expert panel ClinVar classification available

Sources

clinvar ↗

BA1 Variant is absent from gnomAD v2.1 (0/231,580 alleles) and v4.1 (0/1,593,060 alleles). Allele frequency of 0% is far below the BA1 threshold of >1%. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF: 0.000% (0/231
580)
gnomAD v4.1 AF: 0.000% (0/1
593
060)

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 Variant is absent from gnomAD (AF=0%), well below the BS1 threshold of >0.3% allele frequency. Details ▾Hide ▴

Evidence considered

gnomAD AF: 0.000%
below BS1 threshold of >0.3%

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 No data showing this variant observed in healthy adults with full penetrance expected at an early age. The variant is absent from population databases and has only been reported in somatic cancer contexts. Details ▾Hide ▴

Still missing

No observation in healthy adult controls

BS3 Functional studies in PMID:17575125 and PMID:23228967 demonstrate that R465H impairs FBXW7 E3 ubiquitin ligase function, showing loss of function rather than normal function. These studies support a deleterious effect, not a benign one. No studies demonstrate normal protein function for this variant. Details ▾Hide ▴

Evidence considered

PMID:17575125: R465H deficient in Notch1 ICD ubiquitylation
PMID:23228967: R465H deficient in GRα polyubiquitylation

Sources

PMID:17575125 ↗PMID:23228967 ↗

BP1 BP1 applies when a missense variant occurs in a gene where primarily truncating variants cause disease. FBXW7-related neurodevelopmental syndrome and FBXW7-associated cancers are caused by both missense and truncating variants in the WD40 domain. Missense variants at critical arginine residues (Arg465, Arg479, Arg505) are a well-established disease mechanism in FBXW7 (PMID:17575125, PMID:35395208). Details ▾Hide ▴

Evidence considered

FBXW7 missense variants in WD40 domain are a known disease mechanism
Missense at Arg465
Arg479
Arg505 are established pathogenic alterations

Sources

PMID:17575125 ↗

BP2 No data available showing this variant observed in trans with a pathogenic variant. The variant has not been observed in population databases, making it impossible to assess co-occurrence in trans. Details ▾Hide ▴

Still missing

No observation data for trans configuration

BP4 REVEL score of 0.557 predicts a deleterious effect, not a benign one. While BayesDel is below threshold (0.113), the REVEL score provides computational evidence of pathogenicity, not benignity. Multiple in silico predictors do not agree on a benign effect. Details ▾Hide ▴

Evidence considered

REVEL: 0.557 predicts damaging
BayesDel: 0.112528 below deleterious threshold but does not affirm benignity

Sources

revelbayesdel

BP5 BP5 is not applicable — the variant has been observed in somatic cancers (COSMIC: 311 entries, PMID:17575125: 3/26 T-ALL patients) and is classified as Likely Oncogenic by OncoKB. This is not a case where the variant is found in a case with an alternate molecular basis for disease. Details ▾Hide ▴

Evidence considered

COSMIC: 311 somatic entries for this variant
OncoKB: Likely Oncogenic

Sources

oncokb ↗

BP6 ClinVar classification is pathogenic ('Tier I - Strong') by a single submitter (1 star). The user's BP6 rule requires a 3-star expert panel benign or likely benign classification to apply BP6 at supporting strength. The current ClinVar classification supports pathogenicity, not benignity, and is only 1 star. Details ▾Hide ▴

Evidence considered

ClinVar ID 4530533: Tier I - Strong (pathogenic)
1-star single submitter

Sources

clinvar ↗

BP7 BP7 applies to synonymous variants predicted to have no impact on splicing. NM_033632.3:c.1394G>A is a missense variant (p.Arg465His), not a synonymous variant. Although SpliceAI delta is 0.00, BP7 does not apply to missense variants. Details ▾Hide ▴

Evidence considered

Variant type is missense
not synonymous
SpliceAI max delta: 0.00 (not relevant for BP7 on missense)

Sources

spliceai ↗

Not assessed · 7 · no assessment recorded

PS2 No de novo data (with confirmed paternity and maternity) is available for NM_033632.3:c.1394G>A in a germline context. The variant has been observed somatically in T-ALL patients but de novo germline status was not assessed. Details ▾Hide ▴

Still missing

No germline de novo testing data available

Sources

PMID:17575125 ↗

PS4 No case-control or cohort data for this variant in a germline disease context. The variant has been observed in 3/26 pediatric T-ALL patients (PMID:17575125) and in COSMIC (311 somatic entries), but no germline prevalence or case-control data are available for FBXW7-related neurodevelopmental syndrome. Details ▾Hide ▴

Still missing

No germline case-control data for FBXW7-related neurodevelopmental syndrome

Sources

PMID:17575125 ↗

PM6 No de novo data (without confirmed parentage) is available for this variant. The variant has been observed as a somatic mutation in T-ALL (PMID:17575125) but no germline de novo observations have been reported. Details ▾Hide ▴

Still missing

No de novo germline observations reported

Sources

PMID:17575125 ↗

PP1 No segregation data are available for this variant. No family studies have been reported. Details ▾Hide ▴

Still missing

No family segregation data available

PP2 PP2 requires a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. While FBXW7 missense variants in the WD40 domain are known to cause disease (both somatic and germline), gene-level constraint metrics (Z-score, missense depletion) were not available in this case to confirm a low rate of benign missense variation. Details ▾Hide ▴

Still missing

Gene-level missense constraint metrics not available

PP4 No specific phenotype or clinical data for the proband are available to assess whether the patient's phenotype is specific for FBXW7-related disease. Details ▾Hide ▴

Still missing

Patient phenotype data not available

BS4 No segregation data available to evaluate lack of cosegregation with disease. Details ▾Hide ▴

Still missing

No family segregation data available

Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/ANM_033632.3:c.1394G>A is a missense substitution (p.Arg465His), not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). The generic PVS1 framework per PMC6185798 does not apply to missense variants. Details ▾Hide ▴

Evidence considered

Variant is a missense substitution at codon 465 in exon 9
pvs1_variant_assessment confirms bucket='other' and apply_generic_pvs1_framework=false

Sources

pvs1_generic_framework ↗

PM3 N/ASkipped — PM3 applies to recessive disorders with a pathogenic variant in trans; FBXW7-related neurodevelopmental syndrome is autosomal dominant and this variant has not been observed in trans. Details ▾Hide ▴

No further detail was recorded.

PM4 N/ASkipped — PM4 applies to protein length-altering variants (in-frame deletions/insertions, stop-loss); this is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

PM5 N/ANo same-residue comparator variant with established pathogenic classification could be identified. The automated pm5_candidates search found no eligible comparator variants at Arg465. While R465C has been reported as a somatic mutation in the CCRF-CEM cell line (PMID:17575125), it lacks a ClinVar pathogenic classification with expert panel support and does not satisfy PM5 requirements. Details ▾Hide ▴

Evidence considered

pm5_candidates search: found=false
candidates=[]
R465C exists as somatic cell line mutation but lacks ClinVar pathogenic classification

Still missing

No ClinVar entry with expert panel pathogenic classification for an alternate amino acid at Arg465

Sources

pm5_candidatesPMID:17575125 ↗

BP3 N/ASkipped — BP3 applies to in-frame deletions/insertions in repetitive regions; this is a substitution variant. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 is not a recognized criterion in the standard ACMG/AMP 2015 framework (PMID:25741868). De novo evidence is assessed under PS2 (with confirmed parentage) or PM6 (without confirmed parentage). No separate PS5 criterion is applicable. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: FBXW7
Transcript: NM_033632.3
Coding (HGVS c.): NM_033632.3:c.1394G>A
Protein (HGVS p.): NP_361014.1:p.(Arg465His)
GRCh38: chr4:152328232 C>T
GRCh37: chr4:153249384 C>T
ClinVar: 4530533
COSMIC: COSV55891746

Gene diagram

Every interpreted variant in FBXW7, mapped onto the exon structure of NM_033632.3. Select a row to find it on the plot.

FBXW7NM_033632.3

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in FBXW7 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 0 / 1,593,060 alleles AF 0 · 0 homozygotes

gnomAD v2.1 0 / 231,580 alleles AF 0 · 0 homozygotes

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0 · 0 / 1,593,060 alleles · 0 hom

No alternate alleles recorded in the displayed ancestry groups.

gnomAD v2.1

AF 0 · 0 / 231,580 alleles · 0 hom

No alternate alleles recorded in the displayed ancestry groups.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1593060 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/73484 alleles, homozygotes = 0).

gnomAD v2.1

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +157 bp

0.000

SpliceAI acceptor gainat +181 bp

0.000

SpliceAI donor lossat -24 bp

0.000

SpliceAI donor gainat -2 bp

0.000

Pangolin splice lossmagnitude shown

-0.010

Pangolin splice gain

0.000

Other predictors

REVEL: 0.557
BayesDel: 0.113

How the predictions were used

Evidence considered

REVEL: 0.557 (deleterious
above 0.5 threshold)
BayesDel: 0.112528 (below 0.27 deleterious threshold)
SpliceAI max delta: 0.00 (no predicted splice impact)

Still missing

HCI prior not available for this gene
Mixed in silico predictions — REVEL supports
BayesDel does not

Sources

revelbayesdelspliceai ↗

Evidence considered

REVEL: 0.557 predicts damaging
BayesDel: 0.112528 below deleterious threshold but does not affirm benignity

Sources

revelbayesdel

Evidence considered

Variant type is missense
not synonymous
SpliceAI max delta: 0.00 (not relevant for BP7 on missense)

Sources

spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.557. BayesDel score = 0.112528.

8 paper records listed. 2 cited in the classification.

Cited in the classification

The tumor suppressor gene hCDC4 is frequently mutated in human T-cell acute lymphoblastic leukemia with functional consequences for Notch signaling.

Malyukova A et al. · 2007 Jun 15

R465H identified in 3 of 26 pediatric T-ALL patients as a somatic mutation. In vitro functional assays demonstrated the R465H mutant is severely deficient in Notch1 ICD polyubiquitylation compared to wild-type hCdc4 and fails to suppress Notch1 transcriptional activity in a luciferase reporter assay. Codons Arg465, Arg479, and Arg505 are identified as critical arginine residues in the WD40 substrate-binding region.
→ PS3 → PM1 Names this variant
PMID 17575125 ↗
Source detail

each of the mutant alleles was severely deficient in multiubiquitylating Notch1 ICD as compared with wild-type hCdc4

Location Abstract; Table 1 (patients 13-15); Results: nucleotide change description (G to A at codon 465); Figure 1A (SSCP); Figure 1D (ubiquitylation assay); Figure 2A-B (luciferase reporter)

Context In vivo ubiquitylation assay in HCT116 hCDC4-negative colorectal carcinoma cells; Notch1-sensitive luciferase reporter assay in HCT116 and U2OS cells
FBXW7 regulates glucocorticoid response in T-cell acute lymphoblastic leukaemia by targeting the glucocorticoid receptor for degradation.

Malyukova A et al. · 2013 Apr

The R465H FBXW7 mutant was directly tested alongside R479Q and R505C in in vivo ubiquitylation assays. All three arginine mutants were severely deficient in polyubiquitylating the glucocorticoid receptor alpha (GRα) compared to wild-type FBXW7, confirming loss of E3 ligase function. The paper defines GRα as a novel FBXW7 substrate and demonstrates that FBXW7 inactivation enhances glucocorticoid sensitivity in T-ALL.
→ PS3 Names this variant
PMID 23228967 ↗
Source detail

All FBXW7 mutants were severely deficient in polyubiquitylating GRα as compared with WT-FBXW7

Location Materials and Methods: plasmid construction (Flag-FBXW7-R465H); Figure 3c (in vivo ubiquitylation of GRα); Results paragraph on FBXW7 mutants

Context In vivo ubiquitylation assay in HCT116 FBXW7-knockout colorectal carcinoma cells, co-transfected with GRα and HA-ubiquitin

Other recorded publications

Negative regulation of the stability and tumor suppressor function of Fbw7 by the Pin1 prolyl isomerase.

Min SH et al. · 2012

Discusses Pin1-mediated regulation of Fbw7 stability and tumor suppressor function at the gene/protein level. NM_033632.3:c.1394G>A (R465H) was not identified in this paper.
Does not name this variant
PMID 22608923 ↗
Negative regulation of DAB2IP by Akt and SCFFbw7 pathways.

Investigates DAB2IP regulation by Akt and SCFFbw7 pathways at the gene/protein level. NM_033632.3:c.1394G>A (R465H) was not identified in this paper.
Does not name this variant
PMID 24912918 ↗
Systematic Functional Interrogation of Rare Cancer Variants Identifies Oncogenic Alleles.

Describes a systematic functional interrogation platform for rare cancer variants using pooled in vivo tumor formation assays. NM_033632.3:c.1394G>A (R465H) was not identified in this paper.
Does not name this variant
PMID 27147599 ↗
FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors.

Examines FBW7 mutations in T-ALL cell lines mediating NOTCH pathway activation and resistance to gamma-secretase inhibitors at the gene level. NM_033632.3:c.1394G>A (R465H) was not identified in this paper.
Does not name this variant
PMID 17646409 ↗
Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors.

Shern JF et al. · 2014

Reports comprehensive genomic analysis of rhabdomyosarcoma identifying somatic alterations. NM_033632.3:c.1394G>A (R465H) was not identified in this paper.
Does not name this variant
PMID 24436047 ↗
American College of Medical Genetics and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in neoplastic disorders.

No paper-specific finding is recorded.

PMID 23619274 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 0 / 1,593,060 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗

ClinVar Captured ClinVar source record Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

gnomAD v2.1

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar but submission details could not be extracted. (ClinVarID = 4530533)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.557. BayesDel score = 0.112528.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55891746, n = 311 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.